The ets genes encode nuclear phosphoproteins that bind DNA. In an effort to investigate the role of ets proto-oncogenes in cell growth and oncogenesis, we have constructed vectors containing ets-1 and ets-2 genes linked to either the mouse metallothionein promoter or Moloney murine sarcoma virus LTR. By transfection studies using ets-1 vectors we demonstrate that the ets-1 expression transforms NIH 3T3 cells and induces tumors in mice. We also show that the transfection of NIH 3T3 cells with ets-1 expression vectors containing either the metallothionein promoter or Moloney LTR results in the activation of the endogenous ets-I mRNA. Using probes that can distinguish between endogenous and exogenous gene mRNA expression (by Northern blots), we could show that only the endogenous ets-1 gene is activated by the expression of exogenous ets-1, and the expression of ets-2 has no effect on the endogenous ets-1 gene expression. The results indicate that the ets-1 proto-oncogene is positively autoregulated by its products. Autoregulation is a common property of various transcription factors, such as jun (positively autoregulated), and myoD (a sequence-specific protein, positively autoregulated). We have also determined that the ets-1 protein possesses a region of strong homology to a structural domain present in myc, the enhancer binding proteins E12, E47, and to a set of Drosophila development gene products (Twist, daughterless, and the achaete-scute-complex), as well as proteins involved in myogenesis myoD, myf5. All these proteins contain residues that are predicted to form two amphipathic helices (helix I and helix II) separated by a loop. Similar to the "Leucine zipper" present in fos and jun, this region is important for dimerization and DNA binding of these proteins. The ets-1 proteins characterized from human, mouse and chicken all contain the helix-loop-helix motif (HLH). It is likely that the ets-1 may dimerize with one of the containing cellular regulatory factor(s) to generate a heterodimer(s) required for autoregulation and/or transactivation of various heterologous promoters.